Recently in the refining process of a plasma derivative or a biopharmaceutical, there is a need for technology for removing pathogenic agents such as a virus and a pathogenic protein in order to enhance safety. Among the methods for removing pathogenic agents such as a virus is a membrane filtration method. Since the separation operation is conducted, in this membrane filtration method, according to the size of the particles based on the sieve principle, the method is efficacious for all the pathogenic agents irrespective of the type of pathogenic organism as well as the chemical or thermal characteristics of the pathogenic organism. Therefore, industrial utilization of the removal of pathogenic agents using the membrane filtration method has been prevailing in recent years.
Since infection with an infectious virus among pathogenic agents may cause serious diseases, removal of contaminating viruses is highly required. Types of viruses include smallest viruses, such as parvovirus, with a diameter of about 18 to 24 nm, medium-sized viruses, such as Japanese encephalitis virus, with a diameter of about 40 to 45 nm and relatively large viruses, such as HIV, with a diameter of about 80 to 100 nm, etc. In order to remove these virus groups physically by the membrane filtration method, a microporous membrane having a pore size of about 10 to 100 nm is required, and particularly the needs for removing small viruses such as parvovirus are increasing in recent years.
In the meantime, when the membrane filtration method is applied in the refining process of a plasma derivative or a biopharmaceutical, it is desirable not only to enhance the virus removal ability but to allow rapid permeation of a large quantity of physiologically active substances in order to improve productivity.
However, when a subject to be removed is a small virus like parvovirus, since its size is extremely small, as small as 18 to 24 nm, it was difficult to satisfy both of the virus removal performance and the amount and rate of permeation of physiologically active substances by conventional technology.
That is, conventional microporous membranes have drawbacks that they can allow permeation of high-molecular-weight physiologically active substances, such as human immunoglobulin and Factor VIII, at a sufficient permeation rate while they cannot remove small viruses such as parvovirus; or they can remove small viruses such as parvovirus while they cannot allow permeation of high-molecular-weight physiologically active substances, such as human immunoglobulin and Factor VIII, at a substantial permeation rate.
International Publication WO91/16968 pamphlet discloses a process comprising immersing a membrane with a solution containing a polymerization initiator and a hydrophilic monomer, allowing polymerization within micropores, thereby adhering a hydrophilic resin to the surface of the micropores. This method, however, has a defect that the hydrophilic resin merely adheres to the surface of the micropores, and therefore, part of the adhering hydrophilic resin may be dissolved out upon washing out low-molecular weight substances generated in the reaction and hydrophilicity of the membrane may be easily lost. In addition, if a cross-linking agent is used in a large amount and copolymerization is performed in order to prevent dissolution-out, high permeability will not be attained for protein solutions.
JP-A-07-265674 describes a polyvinylidene fluoride film having low adsorptivity for goat immunoglobulin which can effectively remove small particles from a solution. It is described that this film is useful for removing viruses from the solution. According to the Examples thereof, however, this hydrophilic film shows a low adsorptivity for goat immunoglobulin, and does not have sufficient permeability for physiologically active substances such as globulin comparable to the present invention.
JP-A-62-179540 describes a hydrophilic hollow fiber porous membrane comprising a hydrophilic hollow fiber porous membrane composed of polyolefin and side chains containing a neutral hydroxyl group grafted to the membrane. The Examples thereof, however, only describe a hydrophilic microporous membrane having an average pore size of 0.1 to 0.16 μm and does not describe a small pore sized microporous membrane having a maximum pore size of 10 to 100 μm.
JP-A-07-505830 describes a process which comprises irradiating hydrophobic microporous membrane of polyolefin or partially fluorinated polyolefin, etc. with ultraviolet ray and polymerizing a bifunctional monomer which has two reactive groups. According to the above-described method, however, hydrophilicity is lost due to cross-linking in hydrophilic diffusive layer and sufficient filtration rate cannot be attained for a protein solution.
International Publication WO01/14047 pamphlet describes a filtration membrane for physiologically active substances wherein the logarithmic removing ratio for parvovirus is three or more and the permeation ratio for bovine immunoglobulin having a monomer ratio of 80% or more is 70% or more. However, the main membrane disclosed here comprises hollow fibers made of cellulose, and since the mechanical strength when it is wet with water is low, filtration pressure cannot be made high, and therefore, it is very difficult to achieve a high permeation rate.